The present invention is directed toward a novel set of compounds, 5-fluoro-2,4,6-pyrimidinetriamines of Formula I or pharmaceutically acceptable salts thereof (hereinafter referred to as "5-fluoro minoxidil"), which are useful for the treatment of cardiovascular disorders and the promotion of hair growth. The use of minoxidil to treat cardiovascular disorders such as hypertension, congestive hear failure, and angina, peripheral vascular disorders and more recently to promote hair growth was recognized in the past and was extensively patented. Earlier patents to the minoxidil formulae itself are U.S. Pat. Nos. 3,461,461, 3,464,987 and 3,644,364 however they do not disclose or suggest a fluorine substitution even though bromine and chlorine were specifically named and in some cases iodide. Minoxidil for hair growth has also been patented in U.S. Pat. Nos. 4,139,619 and 4,596,812 however the minoxidil formulae claimed and disclosed in those patents did not show a 5-fluoro substituted minoxidil.
One explanation for this apparent deletion from the halogen family was that the fluorine atom was difficult to substitute onto the pyrimidine ring at this particular position.
The subject invention provides a method for substituting fluorine at the 5-position on a minoxidil compound and shows that this particular species has significant advantages over its halogen analogs. The 5-fluoro substituted minoxidil has bene found to have superior transdermal transport properties over unsubstituted minoxidil. The increased amount of minoxidil that is transported into the epidermis means that less can be topically applied to achieve the same hair growth pharmacological efficacy as compared to other non-fluoride substituted minoxidils. Also, because less active ingredient is used, there is significantly reduced side effects when the compound is used for hair growth.